Ketamine for Chronic Pain

Podcast Transcript

Release Date: April 15, 2022
Expiration Date: April 15, 2023
Estimated Time of Completion:  25 minutes

See below to obtain AMA PRA Category 1 Credits™, ANCC Contact Hours, OR Certificate of Participation.

Use of Ketamine for Chronic Pain
Pavan Tankha, DO

Description
Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

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Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation inthe activity.
  
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Podcast Series Director
Imad Najm, MD

Faculty
Pavan Tankha, DO
Center for Spine Health

Agenda
Use of Ketamine for Chronic Pain
Pavan Tankha, DO

Disclosures
In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Foundation Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Imad Najm, MD

Eisai Advisor or review panel participant NIH Research Funding Sunovion Advisor or review panel participant LivaNova, PLC Advisor or review panel participant

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest:

Pavan Tankha, DO

CME Disclaimer
The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity

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Introduction:

Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

The latest data from the Centers for Disease Control and prevention estimates that 20% of US adults suffer from chronic pain, and 8% suffer from high impact chronic pain. Over the past two decades, intravenous ketamine infusion has become a popular treatment option for chronic pain. In today's episode, we're discussing the use of ketamine to manage chronic pain.

Glen Stevens, DO, PhD:

I'm your host Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Pavan Tankha. Dr. Tankha is an anesthesiologist, pain management physician, and medical director for comprehensive pain recovery in Cleveland Clinic's Center for Spine Health. Pavan, welcome to Neuro Pathways.

Pavan Tankha, DO:

Thank you, Glen.

Glen Stevens, DO, PhD:

So ketamine has been around forever. I remember in my early training days, I always looked at it as an anesthetic agent. And one of the things that I remember is that it also had some hallucinogenic properties, and hence unfortunately, also became a drug of abuse. It goes by lots of names. I seem to recall special K as a name. You probably hate all those names. But can you give us a history and tell us how it became a treatment for chronic pain, not just anesthesia?

Pavan Tankha, DO:

So let's start back, actually prior to the synthesis of ketamine. So we're going back to 1956. And in an attempt to find better anesthetics, a medication by the name of phencyclidine is synthesized. That may sound familiar because as a tablet form, it's known as PCP. As a powdered form, it's known as angel dust. And currently, it only has illicit use. Let's go into why it went from a possible anesthetic to an illegal medication.

Pavan Tankha, DO:

So in 1958, scientists decided to study phencyclidine in animals. And what they found was something really quite interesting. In rodents, it caused them to act drunk. In dogs, it caused them to act delirious. In pigeons, they essentially exhibited catalepsy. And in monkeys, it produced general anesthesia. So the scientists at the time, rightfully so, concluded that the mechanism of action of ketamine is likely complex, because it was causing a number of different reactions in different animals. But they decided to move forward with clinical trials in humans to see how it would work out.

And what they found was phencyclidine actually was a very safe anesthetic. However, when patients woke up from the anesthesia, they had very significant emergence delirium. In other words, when you woke up from the anesthesia, you were in a delirium state. And oftentimes, patients would start screaming that they felt their arms or legs had been removed, which as you can imagine, would be quite shocking if you went in for something like an appendectomy or perhaps a facelift. And so they decided given the significant emergence delirium, it didn't make sense to move forward with this medication as a general anesthetic.

However, in 1962, a Dr. Stevens, an organic chemist at Wayne State University, decided to work with the phencyclidine molecule. And he came up with a substance that was initially characterized as CI-581. And what made it unique is it had a ketones and an ammine ring on the molecule. And so if you combine the ketone and ammine, what you get? You get ketamine, right? And so this was found to be the likely best molecule to move forward with, with clinical trials.

So then in 1964, Drs. Domino and Corssen at the University of Michigan asked 20 prison volunteers to do a clinical trial of this medication. And in a dose dependent fashion, they increased the dose of ketamine. And what they found was something very interesting. At a low dose, there was essentially no effect. At a medium dose, a lot of the individuals felt, quote-unquote, "spaced out." And then at a high dose, the ketamine produced general anesthesia. Of note, no one had significant emergence delirium. Which was a win, because that's why phencyclidine was not used subsequently.

Something of note, all the patients, irrespective of their dose, all felt like they were floating in outer space. And anyone who's used ketamine at any dose, low dose or high dose, oftentimes will have patients afterwards say something like, doc, you will not believe this, but I was in space. I was on the moon. I was on Mars. And when you hear it the first time, it's a little troubling. But as it turns out, in the very first clinical trial, this was also reported in all the subjects.

So fast forward to 1970, ketamine is approved by the FDA as a general anesthetic. But shortly thereafter, it was also noted to be abused. In the west coast, and slowly it spread throughout the country, because of its hallucinogenic properties. Again, much phencyclidine or LSD ... they're in the same class. It became readily abused. Around 1994, the first studies for ketamine and pain were starting to be published. In 1999, the DEA, after hearing years of reports of ketamine being misused and abused, made it a scheduled medication, a class three non-narcotic substance. 2000, it was found to have shown antidepressant effects. And fast forward to 2019, S-ketamine was approved by the FDA for intranasal use for treatment resistant depression.

So that's a little bit about the history of ketamine. And if anyone is following along with the math, this makes 60 years since ketamine was first synthesized.

Glen Stevens, DO, PhD:

Yeah. I'll have two comments. One, is I was born in the 50s, so I always like a reference from the 50s. And number two, pigeons, I'm not sure I've heard research studies done on pigeons. And I'm not sure why they chose pigeons, but certainly different.

Pavan Tankha, DO:

Very different, especially the reaction.

Glen Stevens, DO, PhD:

And I know that you mentioned these drugs are all very dirty. You're an anesthesiologist, I always looked at anesthesia drugs as a black box. And what's the main mechanism of action of the ketamine?

Pavan Tankha, DO:

Fantastic question. And so the answer, unfortunately is a little bit more complex. So what we do know about ketamine is it binds to the NMDA receptor. It is a non-competitive antagonist of the NMDA receptor. That receptor is located in multiple areas in the central nervous system. It's found in the dorsal horn of the spinal cord, but it's also found in the thalamus. It's found in the limbic system, it's also found in the prefrontal cortex.

And so when you ask what the mechanism is, in terms of pain, we oftentimes think it's probably the dorsal horn of the spinal cord. Obviously for depression and mood, you're thinking the limbic system. However, as more and more research on ketamine is being done, we've found there are multiple other pathways in which ketamine may be exerting its effect. So as I like to tell patients, more likely than not, NMDA is responsible, but not the exclusive mechanism of action.

Glen Stevens, DO, PhD:

So when we look at patients with chronic pain, I guess it comes down to, how do we factor in who it's time to try a ketamine infusion on, how do we select our patients? Obviously this is the art of medicine.

Pavan Tankha, DO:

Yes, absolutely. I like to say that ketamine is not a first line or even a second line medication, perhaps not even a third line medication for chronic pain. But however, if you've done conservative therapy, if you've tried conventional treatments such as medications, injections, surgery, pain psychology, pain rehabilitation programs, and your pain persists, then ketamine may be a good option.

Oftentimes, it can be integrated in concert with one of those earlier forms of therapy. However, it's not readily available throughout the country. So more often than not, it's something patients come to after they've exhausted other options. As I like to say, if you've given all other reasonable options a try, consider ketamine.

Glen Stevens, DO, PhD:

And are there certain pain, chronic pain condition that work better than others? Global pain versus regional pain, does it make a difference?

Pavan Tankha, DO:

Very, very good question. And so the literature for ketamine and pain is somewhat limited. And because of that, if you go based on simply the literature, the most extensively studied states are complex regional pain syndrome, where it's shown to have a modest benefit. Other neuropathic pain states, such as phantom limb, spinal cord injury, have some data to suggest it may work. Nociceptive pain pathways, such as osteoarthritis, rheumatoid arthritis, again, limited to no data.

Anecdotally, based on my own experience, I've found that ketamine can potentially help with these conditions, but because we don't really understand how it works, we subsequently can't choose the appropriate candidates all the time. But given its good safety profile, I recommend, as I said before, if you've exhausted other methods, give it a try, see if it helps.

Glen Stevens, DO, PhD:

So I'm just curious, when you give ketamine, where do you do it? What's the operation like, how complicated is it?

Pavan Tankha, DO:

Yeah. So we're fortunate to have the capabilities here on the main campus. The S building, the second floor, the infusion suite. It's used primarily for headache infusions. However, we are also doing ketamine infusions there. It is done over a five day period, Monday through Friday. You come in, we start an IV, and we run the ketamine through your bloodstream for approximately 40 minutes. At the end of the infusion, we give you some fluids just to wash it out of your system. And then you can go home. Because ketamine is a general anesthetic, you do need someone to take you back home. Some patients get a little loopy, some patients don't feel anything. But just to be on the safe side, we do ask someone, bring you home.

Pavan Tankha, DO:

The mechanism of action, again, because it is not clear, I usually have patients follow up with me in about two weeks afterwards, to assess what effects it had.

Glen Stevens, DO, PhD:

Okay, excellent. Are there specific contraindications, patients that you will not give it to? Or what are the relative contraindications?

Pavan Tankha, DO:

So the side effects of ketamine are dose dependent. So as the dose increases, side effects are more likely, as are the different effects ketamine may have on your heart rate, your blood pressure, your central nervous system. Thankfully, low dose ketamine, which is what we infuse patients with, have almost no hemodynamic effects. And so at most, we may look into some things that may be precautions. For instance, if a patient has unstable angina, uncontrolled high blood pressure, very significant coronary artery disease, extensive liver failure, psychosis, delirium. Those may be reasons to hold off, especially since this is an elective procedure. However, more often than not, the ketamine is a safe option for patients.

Glen Stevens, DO, PhD:

So chronic pain patients often commingle with mood disorders. And obviously, you had mentioned some that would be a problem with this. But anecdotally, or even published-wise, are you seeing patients reporting improved mood as well as pain, or are they just feeling better because they're not in chronic pain?

Pavan Tankha, DO:

Very good question. And so studies will slowly come out to help elucidate that more. What I've seen is four possible outcomes after the infusion. Patients have a significant improvement in pain. Patients have a significant improvement in mood. Sometimes they have both. Or unfortunately, sometimes they don't have any effect.

And again, because we can't specifically characterize which patients will have an effect, whether it be pain or mood, we have to see how the infusion goes. But I've seen all of those. And more often than not, if a patient comes in with pain but their mood is better, they consider that a win as well.

Glen Stevens, DO, PhD:

So you've partially answered this question, but it's probably a little deeper. What constitutes a positive response then? Do you give them the pain scale and they need to score certain percentage? Is it just, I feel better? What do you guys use?

Pavan Tankha, DO:

In comprehensive pain recovery, we are a functional restoration program. So more often than not, rather than a number or a survey, we ask, what can they do more after the infusion? What has changed in terms of their activities and what they want to do or what they'd like to do? And so I consider that a positive outcome.

Glen Stevens, DO, PhD:

And we mentioned the mood, any other potential benefits of the drug, besides the pain and mood?

Pavan Tankha, DO:

As of right now, no. But there are a number of studies being conducted on ketamine, thankfully, now. And there are a number of studies we'd also like to conduct here, now that we have a standardized protocol at the clinic.

Glen Stevens, DO, PhD:

So side effects, what types of things do we see? I'm sure it runs the gamut, depending on dose and time. But what do we see?

Pavan Tankha, DO:

Absolutely correct. So thankfully, again, at low dose, we don't have to worry about too many side effects. Occasionally patients may develop a headache, nausea isn't completely out of the realm of possibility, though it is rare. As I mentioned from the very first clinical trial of ketamine, patients may feel like they are floating. Rarely do we get to the dose where they're actually having an out of body experience or are in space, but floating isn't unusual.

Aside from that, it's very well tolerated. But again, if you go from the low dose ketamine to moderate to high dose, you can get more side effects such as hallucinations and other issues.

Glen Stevens, DO, PhD:

Do you premed the patients, or no?

Pavan Tankha, DO:

I do. I do. Just to prevent ... in the unlikely event they would have any hallucinations. We do give them a low dose of a benzodiazepine before we begin as well as a anti-nausea medication as well. Just to prevent any possible adverse outcomes or side effects.

Glen Stevens, DO, PhD:

So I suspect there's some formula for a max amount of ketamine over a certain period of time. What's your dosing regimen for, I get a treatment today, when can I get treated again? What's the maximum number of treatments? And I'm sure it's a bit dose dependent.

Pavan Tankha, DO:

It is. So currently we do 0.5 milligrams per kilogram over 40 minutes, over five days. And then we see it's reasonable to repeat it every three to four months, depending on the response. Some patients may get longer response. If it's shorter, it doesn't make sense to repeat it more than that. And so with three to four treatments a year, that seems to be quite reasonable at this time.

Glen Stevens, DO, PhD:

The model seems a little bit like caudal epidural blocks, that you would give a treatment, see how they do. Hopefully they get a few months, and then retreat them if they recur.

Pavan Tankha, DO:

Yes, correct. Correct. Very much so.

Glen Stevens, DO, PhD:

What about addiction? What's my risk of being addicted?

Pavan Tankha, DO:

So currently, again, one of the advantage of low dose ketamine, we do not see any at evidence for addiction or dependence, whether it be physical dependence or psychological dependence. The literature does show ... and again, as I mentioned, as early as the 1970s. Ketamine has been abused. If you are abusing ketamine, there is a risk for psychological dependence with long term use. However, with short term, low dose infusions, we do not see that.

Glen Stevens, DO, PhD:

You know, I've heard about detachment issues with people on ketamine. Do you see that with the low dose infusions?

Pavan Tankha, DO:

We do not. Are you referring to perhaps the dissociative anesthetic aspect?

Glen Stevens, DO, PhD:

Yeah.

Pavan Tankha, DO:

So interestingly enough, there was a paper written about a decade ago by Dr. Domino. As I mentioned, the first clinical trial was done by Dr. Domino and Corssen. And he mentioned describing what patients would look like. They'd be seemingly awake, but they wouldn't respond to stimuli. And he was mentioning this to his wife, who he says, came up with a term dissociative anesthesia. And so Park-Davis, the company that was trying to get ketamine improved by the FDA, was a little hesitant of introducing this new term, fearing that the FDA may say, what does this actually mean, or what of the implications? But that term has stuck around since it was introduced.

Glen Stevens, DO, PhD:

So you brought it up, so it's probably a good thing to just discuss the FDA. What's the FDA approval for ketamine?

Pavan Tankha, DO:

Currently ketamine is approved as a general anesthetic and for sedation. And more recently in 2019, S-ketamine has been approved for intranasal use for treatment resistant depression. Using ketamine for chronic pain is currently an off-label use.

Glen Stevens, DO, PhD:

So we have a lot of physicians, obviously, listening to the podcast that may have an interest. Reimbursement for the procedure, complicated, not complicated, variable?

Pavan Tankha, DO:

Variable. We have not run into any major issues with reimbursement thus far. But the reimbursement is quite variable from carrier to carrier.

Glen Stevens, DO, PhD:

And let's say you treat me with ketamine and I get a nice response, I'm doing well with it. What's the likelihood I'll be on some form of ketamine long term? Or is it the hope that you'll do a treatment dosage and then stop and use other pain treatments?

Pavan Tankha, DO:

We'd like to think of ketamine as one arrow in the pain management quiver, if you will. Oftentimes for chronic pain, we approach it comprehensively. So there's not only self-care, diet, activity, sleep, but there's things providers can help with. Medications, pain psychology, and again, the ketamine. More often than not, it is something that needs to be repeated long term.

We're hoping, however, with some of the studies coming out and some of the newer formulations, perhaps this is something that can be used at home safely as needed. But currently, it is something that needs to be repeated, along with the other techniques we use for chronic pain management.

Glen Stevens, DO, PhD:

And are there age limits for utilizing the drug? Probably not used in children, but maybe it is?

Pavan Tankha, DO:

Correct. It has been used in children. My area of expertise as in adults only, and so I have not infused it for chronic pain for children. But I don't see any reason why it could not be safely used, as it is titrated based on weight.

Glen Stevens, DO, PhD:

And is there an upper age limit, or no?

Pavan Tankha, DO:

Interestingly enough, the oldest patient I infused with ketamine was when I was in Connecticut, practicing in Connecticut. He was a World War II veteran, he was in his late 90s. At the end of the infusion, I still remember, he mentioned, well, that was fun. And so, because it is so well tolerated at a low dose, there does not seem to be an upper age limit, thankfully.

Glen Stevens, DO, PhD:

Nice. So any, besides the ketamine, other new treatment options on the horizon that we should know about?

Pavan Tankha, DO:

At this point, no. It's more formulations of the ketamine. One of the reasons ketamine tablets aren't used as frequently, again, because of the abuse potential and limited trials. The S-ketamine, the intranasal spray has a great deal of interest. There are a number of clinical trials going on with that for chronic pain. Hopefully the idea is to get something that is safe, that a patient can use at home as needed, while also minimizing abuse potential. I think that would be the ultimate goal for this.

Glen Stevens, DO, PhD:

And what about oral administration of the drug?

Pavan Tankha, DO:

Yes. It has poor bio-availability, only about 20, 25% bio-available when taken by mouth. And because of the potential abuse, it's not really been studied that extensively. But theoretically, it could be. If there was some way it wouldn't be abused, that may be an option in the future.

Glen Stevens, DO, PhD:

And is there an antidote for the drug itself, or no? Like narcotics do, does this have an antidote?

Pavan Tankha, DO:

It does not. So interestingly enough, when compared to phencyclidine, ketamine is only about a 10th as potent. And it's very short acting, so the effects wear off within 10 to 15 minutes. A good example of this is when I was doing OB anesthesia, sometimes if a C-section was going on and the spinal failed, you could use ketamine. Which would provide anesthesia to the mother, but you would have to redose it, roughly every 10 minutes. And so very quick onset, very quick offset.

Glen Stevens, DO, PhD:

Pavan, I really enjoyed the discussion today. Are there any additional closing responses you'd like to make?

Pavan Tankha, DO:

As I like to remind patients, chronic pain is a complex disease state, and oftentimes one treatment modality does not provide the benefit the patient is looking for. So we highly recommend a multimodal treatment response, including self-care. Which includes optimizing diet, optimizing activity, optimizing sleep, as well as things we can provide. That includes medication optimization, pain psychology, as well as ketamine.

Glen Stevens, DO, PhD:

Well, Pavan, it's been a real pleasure. I've learned a lot and I'm sure our audience says as well. Thank you for joining me today.

Pavan Tankha, DO:

Thank you, Glen.

Conclusion:

This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.